The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.

BACKGROUND: Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36). METHODS: Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed. RESULTS: Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001). LIMITATIONS: Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal. CONCLUSIONS: Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.

A gender-based secondary analysis of the ADAPT-2 combination naltrexone and bupropion treatment for methamphetamine use disorder trial.

BACKGROUND AND AIMS: Socio-cultural (gender) and biological (sex)-based differences contribute to psychostimulant susceptibility, potentially affecting treatment responsiveness among women with methamphetamine use disorder (MUD). The aims were to measure (i) how women with MUD independently and compared with men respond to treatment versus placebo and (ii) among women, how the hormonal method of contraception (HMC) affects treatment responsiveness. DESIGN: This was a secondary analysis of ADAPT-2, a randomized, double-blind, placebo-controlled, multicenter, two-stage sequential parallel comparison design trial. SETTING: United States. PARTICIPANTS: This study comprised 126 women (403 total participants); average age = 40.1 years (standard deviation = 9.6) with moderate to severe MUD. INTERVENTIONS: Interventions were combination intramuscular naltrexone (380 mg/3 weeks) and oral bupropion (450 mg daily) versus placebo. MEASUREMENTS: Treatment response was measured using a minimum of three of four negative methamphetamine urine drug tests during the last 2 weeks of each stage; treatment effect was the difference between weighted treatment responses of each stage. FINDINGS: At baseline, women used methamphetamine intravenously fewer days than men [15.4 versus 23.1% days, P = 0.050, difference = -7.7, 95% confidence interval (CI) = -15.0 to -0.3] and more women than men had anxiety (59.5 versus 47.6%, P = 0.027, difference = 11.9%, 95% CI = 1.5 to 22.3%). Of 113 (89.7%) women capable of pregnancy, 31 (27.4%) used HMC. In Stage 1 29% and Stage 2 5.6% of women on treatment had a response compared with 3.2% and 0% on placebo, respectively. A treatment effect was found independently for females and males (P < 0.001); with no between-gender treatment effect (0.144 females versus 0.100 males; P = 0.363, difference = 0.044, 95% CI = -0.050 to 0.137). Treatment effect did not differ by HMC use (0.156 HMC versus 0.128 none; P = 0.769, difference = 0.028, 95% CI -0.157 to 0.212). CONCLUSIONS: Women with methamphetamine use disorder receiving combined intramuscular naltrexone and oral bupropion treatment achieve greater treatment response than placebo. Treatment effect does not differ by HMC.

Overcoming Challenges to Treat Inadequate Response in Major Depressive Disorder.

​​ ​​ When a patient with major depressive disorder experiences inadequate response to an antidepressant, clinicians should employ measurement-based care strategies to improve outcomes. Evidence suggests that adjunctive therapies, such as the FDA-approved atypical antipsychotics, are efficacious when the initial treatment is well tolerated but not improving symptoms. Clinicians should consult guidelines, peer-reviewed journals, CME programs, and other sources to stay up-to-date with current and emerging treatments in this area. They should also be familiar with the available options for psychotherapy, neurostimulation, supplements, and exercise for patients who prefer alternative therapies. ​​.

Double-blind, proof-of-concept (POC) trial of Low-Field Magnetic Stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD).

BACKGROUND: Low-Field Magnetic Stimulation (LFMS) is a novel, non-invasive, sub-threshold neuromodulation technique, shown in preliminary studies to have immediate mood elevating effects in both unipolar and bipolar depressed patients. OBJECTIVE: We aimed to assess the antidepressant augmentation effects at 48 h of LFMS administered on two consecutive days compared to sham treatment in treatment resistant depression (TRD) subjects, using the Sequential Parallel Comparison Design (SPCD). METHODS: Eighty-four eligible subjects with TRD were randomly assigned to double-blind treatment with LFMS 20 min/day for four days, sham treatment 20 min/day for four days, or sham treatment 20 min/day for 2 days followed by LFMS treatment 20 min/day for two days, using the pre-randomization version of the SPCD (randomization 1:1:1). The SPCD analyses used a repeated measures linear modeling approach with maximum likelihood estimation to use all available data, and using a 60-40 weighting of Stage 1 vs. 2 responses, with the primary outcome being measured after 2 and 4 days. RESULTS: Both primary and secondary outcome measures consistently showed no differences between LFMS-treated patients and those treated with sham, with the exception of a slight, non-significantly greater improvement than sham in the visual analogue scale (VAS) sad mood on LFMS-treated patients. LFMS treatment was relatively well tolerated. CONCLUSIONS: We did not observe a significantly greater, rapid efficacy of LFMS compared to sham therapy. Future studies need to examine the possible therapeutic effects of more intensive forms of LFMS, as other forms of neurostimulation typically require longer duration of exposure.

Measurement, Education and Tracking in Integrated Care (METRIC): use of a culturally adapted education tool versus standard education to increase engagement in depression treatment among Hispanic patients: study protocol for a randomized control trial.

BACKGROUND: Significant mental health disparities exist for Hispanic populations, especially with regard to depression treatment. Stigma and poor communication between patients and their providers result in low use of antidepressant medications and early treatment withdrawal. Cultural factors which influence treatment decisions among Hispanics include fears about the addictive and harmful properties of antidepressants, worries about taking too many pills, and the stigma attached to taking medications. Primary care settings often are the gateway to identifying undiagnosed or untreated mental health disorders, particularly for people with co-morbid physical health conditions. Hispanics, in particular, are more likely to receive mental healthcare in primary care settings. Recent recommendations from the U.S. Preventive Services Task Force are that primary care providers screen adult patients for depression only if systems are in place to ensure adequate treatment and follow-up. METHODS: We are conducting a randomized controlled trial among 150 depressed adult Hispanics in a primary care safety net setting, testing the effectiveness of a culturally appropriate depression education intervention to reduce stigma and increase uptake in depression treatment among Hispanics, and implement a Measurement-Based Integrated Care (MBIC) model with collaborative, multidisciplinary treatment and culturally tailored care management strategies. DISCUSSION: This study protocol represents the first randomized control trial of the culturally adapted depression education fotonovela, Secret Feelings, among Hispanics in a primary care setting. The education intervention will be implemented after diagnosis using an innovative screening technology and enrolled in measurement-based integrated care for the treatment of depression, which will help build the evidence around cultural adaptations in treatment to reduce mental health disparities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02702596. Registered on 20 March 2016.

Demonstrating test-retest reliability of electrophysiological measures for healthy adults in a multisite study of biomarkers of antidepressant treatment response.

Growing evidence suggests that loudness dependency of auditory evoked potentials (LDAEP) and resting EEG alpha and theta may be biological markers for predicting response to antidepressants. In spite of this promise, little is known about the joint reliability of these markers, and thus their clinical applicability. New standardized procedures were developed to improve the compatibility of data acquired with different EEG platforms, and used to examine test-retest reliability for the three electrophysiological measures selected for a multisite project-Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC). Thirty-nine healthy controls across four clinical research sites were tested in two sessions separated by about 1 week. Resting EEG (eyes-open and eyes-closed conditions) was recorded and LDAEP measured using binaural tones (1000 Hz, 40 ms) at five intensities (60-100 dB SPL). Principal components analysis of current source density waveforms reduced volume conduction and provided reference-free measures of resting EEG alpha and N1 dipole activity to tones from auditory cortex. Low-resolution electromagnetic tomography (LORETA) extracted resting theta current density measures corresponding to rostral anterior cingulate (rACC), which has been implicated in treatment response. There were no significant differences in posterior alpha, N1 dipole, or rACC theta across sessions. Test-retest reliability was .84 for alpha, .87 for N1 dipole, and .70 for theta rACC current density. The demonstration of good-to-excellent reliability for these measures provides a template for future EEG/ERP studies from multiple testing sites, and an important step for evaluating them as biomarkers for predicting treatment response.

Brief, unidimensional melancholia rating scales are highly sensitive to the effect of citalopram and may have biological validity: implications for the research domain criteria (RDoC).

BACKGROUND: Most depression rating scales are multidimensional and the resulting heterogeneity may impede identification of coherent biomarkers. The aim of this study was to compare the psychometric performance of the multidimensional 17-item Hamilton Depression Rating Scale (HAM-D17) and the 30-item Inventory of Depressive Symptomatology (IDS-C30) to that of their unidimensional six-item melancholia subscales (HAM-D6 and IDS-C6). METHODS: A total of 2242 subjects from level 1 (citalopram) of the Sequenced Treatment Alternatives to Relieve Depression (STAR* study were included in the analysis. Symptom change, response and remission rates were compared for HAM-D6 versus HAM-D17 and for IDS-C6 versus IDS-C30. The changes in total scores on these scales were compared to the change in Quality of Life Enjoyment and Satisfaction Questionnaire (QLES-Q) score using correlation analysis. RESULTS: The response to treatment was significantly greater according to the HAM-D6 and IDS-C6. Furthermore, the correlation of changes in depression-ratings with changes in QLES-Q scores were comparable for the subscales and full scales. LIMITATIONS: STAR*D was not designed to answer the research questions addressed in this analysis. CONCLUSIONS: Our findings indicate that the HAM-D6 and IDS-C6 melancholia scales capture a coherent construct in depression. The syndrome reflected in these scales is unidimensional, sensitive to specific pharmacological intervention, and therefore likely to have biological validity. We therefore believe that "melancholia" thus defined could be a valuable construct under the Research Domain Criteria (RDoC), which specifically aims at identifying the neurobiology underlying mental disorders and providing drugable targets.

Evidence-based recommendations for the prescription of exercise for major depressive disorder.

Major depressive disorder (MDD) is a source of great disease burden, due in part to the limited accessibility and effectiveness of current treatments. Although current treatments are efficacious in a segment of the population with MDD, there is a clear need for alternative and augmentation treatment strategies. Exercise is one such alternative treatment option. Research has shown exercise to be efficacious as both a stand-alone and an augmentation therapy. As a result, exercise is now included in the American Psychiatric Association's treatment recommendations. The purpose of this article is to provide clinicians with a knowledge base to prescribe exercise to their patients. The authors describe the evidence supporting the use of exercise in the treatment of MDD, provide evidence-based recommendations for prescribing exercise, and address practical considerations related to prescribing exercise in real-world treatment settings.

The effect of sildenafil on quality of life.

BACKGROUND: Antidepressant-induced sexual dysfunction affects approximately 50% of patients taking antidepressants. Previous research has explored sildenafil's effectiveness in treating various forms of erectile dysfunction, but there is no research supporting sildenafil's use for improving the quality of life for patients with sexual dysfunction linked to antidepressant use. The authors of this article aimed to assess the improvements in quality of life in patients taking sildenafil to treat antidepressant-induced sexual dysfunction. METHODS: One hundred and two out of 2,239 male and female patients in the follow-up phase of the Sequenced Treatment Alternatives to Relieve Depression antidepressant trials who complained of sexual dysfunction were given sildenafil, 50 to 100 mg, as needed. After 12 months, we measured patients' change in libido, sexual drive, family relationships, overall well-being, satisfaction with treatment, and overall contentment with items on the 17-item Hamilton Depression Rating Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, 30-item Inventory of Depressive Symptoms, and 12-item Short Form Health Survey. RESULTS: There was a significant association between sildenafil use and improvement in libido and sexual drive by month 6. There was no significant improvement in the quality-of-life scores we examined, but treatment satisfaction and overall contentment increased over time. CONCLUSIONS: Despite no direct association with sildenafil use and quality-of-life scores, sildenafil may be a beneficial treatment for antidepressant-induced sexual dysfunction. A double-blind, placebo-controlled study of sildenafil in antidepressant-induced sexual dysfunction is needed to further explore its potential benefits.

Prospective trial of equine-assisted activities in autism spectrum disorder.

BACKGROUND: Anecdotal reports and some studies suggest that equine-assisted activities may be beneficial in autism spectrum disorders (ASD). OBJECTIVE: To examine the effects ofequine-assisted activities on overall severity of autism symptoms using the Childhood Autism Rating Scale (CARS) and the quality ofparent-child interactions using the Timberlawn Parent-Child Interaction Scale. In addition, this study examined changes in sensory processing, quality of life, and parental treatment satisfaction. DESIGN AND PARTICIPANTS: Children with ASD were evaluated at four time points: (1) before beginning a 3-to-6 month waiting period, (2) before starting the riding treatment, and (3) after 3 months and (4) 6 months of riding. Twenty-four participants completed the waiting list period and began the riding program, and 20 participants completed the entire 6 months of riding. Pretreatment was compared to posttreatment with each child acting as his or her own control. RESULTS: A reduction in the severity of autism symptoms occurred with the therapeutic riding treatment. There was no change in CARS scores during the pretreatment baseline period; however, there was a significant decrease after treatment at 3 months and 6 months of riding. The Timberlawn Parent-Child Interaction Scale showed a significant improvement in Mood and Tone at 3 months and 6 months of riding and a marginal improvement in the reduction of Negative Regard at 6 months of riding. The parent-rated quality of life measure showed improvement, including the pretreatment waiting period. All of the ratings in the Treatment Satisfaction Survey were between good and very good. CONCLUSION: These results suggest that children with ASD benefit from equine-assisted activities.

Antenatal depression: a rationale for studying exercise.

BACKGROUND: Major depressive disorder (MDD) in pregnancy or antenatal depression poses unique treatment challenges and has serious consequences for mothers, unborn babies, and families when untreated. This review presents current knowledge on exercise during pregnancy, antidepressant effects of exercise, and the rationale for the specific study of exercise for antenatal depression. METHOD: A systematic literature review was performed using English language articles published in Medline, PsycINFO, CINAHL, and the Cochrane Library from 1985 to January 2010. RESULTS: There is a broad literature supporting the antidepressant effects of exercise, but a paucity of studies specifically for antenatal depression. A small number of observational studies have reported that regular physical activities improve self-esteem and reduce symptoms of anxiety and depression during pregnancy. To date, there have not been randomized controlled studies of exercise for the treatment of MDD in pregnant women. CONCLUSIONS: Systematic studies are needed to assess exercise as a treatment alternative for MDD during pregnancy. In consideration of the benefits of exercise for the mother and baby, and the burden of depression, studies are needed to determine the role of exercise for pregnant women with depression.

Complementary and alternative medicine in major depressive disorder: the American Psychiatric Association Task Force report.

OBJECTIVE: To review selected complementary and alternative medicine (CAM) treatments for major depressive disorder (MDD). PARTICIPANTS: Authors of this report were invited participants in the American Psychiatric Association's Task Force on Complementary and Alternative Medicine. EVIDENCE: The group reviewed the literature on individual CAM treatments for MDD, methodological considerations, and future directions for CAM in psychiatry. Individual CAM treatments were reviewed with regard to efficacy in MDD, as well as risks and benefits. Literature searches included MEDLINE and PsycINFO reviews and manual reference searches; electronic searches were limited to English-language publications from 1965 to January 2010 (but manual searches were not restricted by language). Treatments were selected for this review on the basis of (1) published randomized controlled trials in MDD and (2) widespread use with important clinical safety or public health significance relevant to psychiatric practice. An action plan is presented based on needs pertaining to CAM and psychiatry. CONSENSUS PROCESS: Consensus was reached by group conferences. Written iterations were drafted and sent out among group members prior to discussion, resolution of any differences of interpretation of evidence, and final approval. CONCLUSIONS: A review of randomized controlled trials for commonly used CAM treatments such as omega-3 fatty acids, St John's wort (Hypericum), folate, S-adenosyl-L-methionine (SAMe), acupuncture, light therapy, exercise, and mindfulness psychotherapies revealed promising results. More rigorous and larger studies are recommended. Each CAM treatment must be evaluated separately in adequately powered controlled trials. At this time, several CAM treatments appear promising and deserve further study. The greatest risk of pursuing a CAM therapy is the possible delay of other well-established treatments. Clinical, research, and educational initiatives designed to focus on CAM in psychiatry are clearly warranted due to the widespread use of CAM therapies.

Folate and unipolar depression.

BACKGROUND: Although major depressive disorder (MDD) is a treatable disease, the remission rates associated with antidepressant monotherapy are still far from optimal. Folate is an inexpensive, easily tolerated natural augmenting agent, which has been reported to improve medication treatment outcomes in patients with MDD. OBJECTIVE: The aim of this study was to review the literature on the clinical utility of folate augmentation for patients with MDD. FOLATE AND DEPRESSION: Patients with depression have consistently been found to have lower levels of serum and red blood cell folate than normal or nondepressed psychiatric patients. Decreased folate levels have been associated with lowered response rates to standard antidepressant pharmacotherapy. Recent studies have shown that augmentation with a folate supplement increases medication response in both treatment-naïve and treatment-resistant depressed patients irrespective of whether there is folate deficiency. CONCLUSIONS: Depressed patients with both low and normal folate levels may benefit from augmenting a primary antidepressant medication either initially, at the onset of treatment, or later after some degree of treatment resistance has been recognized.

A direct comparison of presenting characteristics of depressed outpatients from primary vs. specialty care settings: preliminary findings from the STAR*D clinical trial.

PURPOSE: No study has directly compared the clinical features of depression for patients entering clinical trials using identical enrollment criteria at primary care (PC) and specialty care (SC) settings. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (http://www.star-d.org) provides a unique opportunity to provide this comparison for patients with a major depressive disorder (MDD) requiring treatment. SUBJECTS AND METHODS: We report baseline data for the first 1500 patients enrolled in this trial involving 41 clinic sites (18 PC, 23 SC). Broadly inclusive eligibility criteria required that patients have a DSM-IV diagnosis of nonpsychotic MDD, have not failed an adequate medication trial during their current episode and score>or=14 on the 17-item Hamilton Rating Scale for Depression (HAM-D17). Primary outcomes included the 30-item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) and the HAM-D17. RESULTS: Specialty care and PC patients had equivalent degrees of depressive severity (IDS-C30=35.8; HAM-D17=20.4). Specialty care patients were almost twice as likely to report a prior suicide attempt than PC patients (21% vs. 12%, P<.0001) and slightly less likely to endorse suicidal ideation in the past week (45.0% vs. 50.8%, P=.006). The only other distinguishing core symptoms were a slightly lower likelihood of PC patients endorsing depressed mood (95.2% vs. 97.7%, P=.032) or anhedonia (66.3% vs. 70.7%, P=.042, IDS-C30) and a lower likelihood of PC patients endorsing weight loss (IDS-C30). HAM-D17 results were identical. CONCLUSION: Depressive severity was not different, and symptomatic presentations did not differ substantially. Major depressive disorder is more similar than different among patients at SC and PC settings. Thus, similar clinical and research methods for screening, detecting and measuring treatment outcomes can be applied in both settings.

Prevalence and clinical correlates of irritability in major depressive disorder: a preliminary report from the Sequenced Treatment Alternatives to Relieve Depression study.

BACKGROUND: Irritability is a common feature of major depressive disorder (MDD), though it is not included in the DSM-IV diagnostic criteria for adult MDD and is not assessed in most standard depression rating scales. Irritability with or without depression has been associated with risk for suicide, violence, and cardiovascular disease. METHOD: The prevalence of significant levels of irritability was examined among the first 1456 outpatients with nonpsychotic MDD entering the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Sociodemographic and clinical features were compared for participants who did and did not report irritability at least 50% of the time during the week preceding study entry. RESULTS: Of 1456 evaluable subjects, 582 (40%) reported irritability more than half the time. These individuals were more likely than nonirritable subjects to be female, to be younger, to be unemployed, and to report a history of at least 1 suicide attempt. Functional status and quality of life were also poorer in this group. Irritability was correlated with overall depressive severity, which accounted for nearly all of the clinical differences noted, with the exception of vascular disease, for which the association persisted after controlling for age, sex, and depressive severity. CONCLUSION: Irritability is prevalent among depressed outpatients and associated with a greater likelihood of suicide attempts, poorer functional status, and greater prevalence of vascular disease. It is correlated with overall depression severity and thus may not represent a distinct depressive subtype per se. The impact of irritability on course and treatment outcome merits further study.

Methods of testing feasibility for sequenced treatment alternatives to relieve depression (STAR*D).

In large multi-site trials, a feasibility or pilot study can be crucial to test the functionality of all aspects of conducting the study prior to the initiation of the formal study. A feasibility trial was conducted for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Project, a multi-site, prospective, sequentially randomized, clinical trial of outpatients with nonpsychotic major depressive disorder. From 14 December 2000 to 8 June 2001, 42 patients were screened for enrollment into the STAR*D Feasibility Trial. Twenty-four patients who were eligible and consented to participate were treated with citalopram for up to 12 weeks. During the course of this trial, issues were raised that resulted in modifications to the study procedures. Modifications made as a result of this trial affected four domains: (1) communication, (2) patient and provider burden, (3) data collection forms, and (4) recruitment and retention of subjects. This paper describes what was learned during the STAR*D Feasibility Trial so researchers planning to conduct similar trials can learn the practical issues related to conducting such a research project. While the information gathered was useful, it did delay the initiation of the formal trial. We view this cost as an investment in the development of overall study procedures that should lead to a stronger study.

Treatment-resistant depression: new therapies on the horizon.

Managing patients with treatment-resistant depression (TRD) remains a major challenge for the practicing physician. Depression is considered treatment-resistant when at least two adequate monotherapy trials with drugs from different pharmacologic classes fail to elicit a therapeutic response. Although determining the stage of TRD may allow concise description of a patient's antidepressant history, management of TRD is better served by recent attempts to create a treatment algorithm that encompasses definitive diagnosis of true TRD and strategies for optimizing available therapies, including consideration of novel treatment options. Present strategies for managing TRD include optimization of the initial drug, substitution of another drug from the same or a different antidepressant class, combination of two antidepressants with different mechanisms of action, and adding an antidepressant drug from another class. Potential nonpharmacologic treatments include vagus nerve stimulation, repetitive transcranial magnetic stimulation, and magnetic seizure therapy as an alternative to electroconvulsive therapy. Several neuropeptides and their receptors have also been identified as potential targets for pharmacologic intervention, including corticotropin-releasing factor and substance P. Other treatments currently under investigation include augmentation of antidepressant therapy with an atypical antipsychotic agent such as olanzapine or risperidone. This kind of therapeutic intervention may prove to be especially useful in treating patients with TRD.

Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study.

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) attempts to fill in major clinical information gaps and to evaluate the theoretical principles and clinical beliefs that currently guide pharmacotherapy of major depressive disorder. The study is conducted in representative participant groups and settings using clinical management tools that easily can be applied in daily practice. Outcomes include clinical outcomes and health care utilization and cost estimates. Research findings should be immediately applicable to, and easily implemented in, the daily primary and specialty care practices. This article provides the overall rationale for STAR*D and details the rationale for key design, measurement, and analytic features of the study.

Catching up on health outcomes: the Texas Medication Algorithm Project.

OBJECTIVE: To develop a statistic measuring the impact of algorithm-driven disease management programs on outcomes for patients with chronic mental illness that allowed for treatment-as-usual controls to "catch up" to early gains of treated patients. DATA SOURCES/STUDY SETTING: Statistical power was estimated from simulated samples representing effect sizes that grew, remained constant, or declined following an initial improvement. Estimates were based on the Texas Medication Algorithm Project on adult patients (age > or = 18) with bipolar disorder (n = 267) who received care between 1998 and 2000 at 1 of 11 clinics across Texas. STUDY DESIGN: Study patients were assessed at baseline and three-month follow-up for a minimum of one year. Program tracks were assigned by clinic. DATA COLLECTION/EXTRACTION METHODS: Hierarchical linear modeling was modified to account for declining-effects. Outcomes were based on 30-item Inventory for Depression Symptomatology-Clinician Version. PRINCIPAL FINDINGS: Declining-effect analyses had significantly greater power detecting program differences than traditional growth models in constant and declining-effects cases. Bipolar patients with severe depressive symptoms in an algorithm-driven, disease management program reported fewer symptoms after three months, with treatment-as-usual controls "catching up" within one year. CONCLUSIONS: In addition to psychometric properties, data collection design, and power, investigators should consider how outcomes unfold over time when selecting an appropriate statistic to evaluate service interventions. Declining-effect analyses may be applicable to a wide range of treatment and intervention trials.